Tertiary amino compounds having opioid receptor affinity

ABSTRACT

Disclosed are compounds of the formula (I)                  
 
wherein R 1 , R 2  R 3  R 4  R 5 , R 6  and N are as disclosed herein. The compounds are useful for the treatment of chronic and acute pain.

This application claims the benefit of U.S. provisional No. 60/169,396filed Dec. 6, 1999, the disclosure of which is hereby incorporated byreference.

BACKGROUND OF THE INVENTION

Chronic pain is a major contributor to disability in the industrializedworld and is the cause of an untold amount of suffering. The successfultreatment of severe and chronic pain is a primary goal of the physicianwith opioid analgesics being the current drugs of choice. Unfortunately,this class of compounds produces several undesirable side effectsincluding respiratory depression, constipation, and the development oftolerance and dependence.

Opioids are derived from the opium poppy papaya somniferum and includedrugs such as morphine, codeine and semi-synthetic compounds derivedfrom them and from thebaine, another component of the opium poppy. Itwas hypothesized that the opioids derived their therapeutic effect byinteracting with specific receptor sites in the body. Later experimentsled to the belief that there were more than one receptor site in thebody, in explanation for the fact that the synthetic compound nalorphineprovides analgesic activity while at the same time, antagonizes theanalgesic effect of morphine.

Until recently, there was evidence of three major classes of opioidreceptors in the central nervous system (CNS), with each class havingsubtype receptors. These receptor classes were designated as μ, δ and k.As opiates had a high affinity to these receptors while not beingendogenous to the body, research followed in order to identify andisolate the endogenous ligands to these receptors. These ligands wereidentified as enkephalins, endorphins and dynorphins.

Recent experimentation has led to the identification of a cDNA encodingan opioid receptor-like (ORL1) receptor with a high degree of homologyto the known receptor classes. This newly discovered receptor wasclassified as an opioid receptor based only on structural grounds, asthe receptor did not exhibit pharmacological homology. It was initiallydemonstrated that non-selective ligands having a high affinity for μ, δand k receptors had low affinity for the ORL1. This characteristic,along with the fact that an endogenous ligand had not yet beendiscovered, led to the term “orphan receptor”.

The science relating to opioid receptors presents an opportunity in drugdiscovery for novel compounds which can be administered for painmanagement or other syndromes modulated by these receptor. Such drugdiscovery could lead to compounds having a higher affinity for the μ, δand k receptors than known compounds, while producing less side effects.

OBJECTS AND SUMMARY OF THE INVENTION

It is accordingly an object of the present invention to provide newcompounds which exhibit affinity for opioid receptors.

It is another object of the present invention to provide new compoundswhich exhibit affinity for the opioid μ receptor.

It is another object of the present invention to provide new compoundsfor treating a patient suffering from chronic or acute pain byadministering a compound having affinity for the opioid μ receptor.

It is another object of the invention to provide new compounds whichhave agonist activity at the μ receptor which is greater than compoundscurrently available e.g. morphine.

It is another object of the invention to provide methods of treatingchronic and acute pain by administering compounds which have agonistactivity at the μ receptor which is greater than compounds currentlyavailable.

It is another object of the invention to provide methods of treatingchronic and acute pain by administering non-opioid compounds which haveagonist activity at the μ receptor and which produce less side effectsthan compounds currently available.

It is another object of the invention to provide a method of reducingside effects associated with the administration of opioid analgesics ina human patient comprising administering to said human patient ananalgesically effective amount of a non-opioid compound which exhibits abinding affinity specificity for the μ receptor as compared to the δ₂receptor (K_(l) (nM) at the δ₂ receptor/K_(l) (nM) at the μ receptor) ofgreater than about 250.

It is another object of the present invention to provide compoundsuseful as analgesics, antiinflammatories, diuretics, anesthetics andneuroprotective agents and methods for administering said compounds.

Other objects and advantages of the present invention will becomeapparent from the following detailed description thereof. With the aboveand other objects in view, the present invention comprises compoundshaving the general formula (I):

wherein

R₁ is selected from the group consisting of a bond and C₁₋₁₀ alkyl,alkenyl or alkenylene;

R₂ and R₃ are independently selected from the group consisting ofhydrogen and C₁₋₁₀ alkyl, alkenyl or alkenylene

R₄ is selected from the group consisting of a bond and C₁₋₁₀ alkyl,alkenyl or alkenylene, said C₁₋₁₀ alkyl, alkenyl or alkenyleneoptionally substituted with 1–3 halogen or oxo groups;

R₅ is selected from the group consisting of hydrogen, a 5 or 6 memberedaromatic or heteroaromatic group, and a C₃₋₁₂ cycloalkyl;

R₆ is selected from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl and halogen; and

N is an integer from 0–3; and pharmaceutically acceptable salts thereof.

In preferred embodiments R₁ is selected from methyl or ethyl.

In other preferred embodiments R₂ is selected from methyl, ethyl, propyland butyl.

In other preferred embodiments R₄ is selected from a bond, methyl orethyl, wherein the methyl and ethyl are optionally substituted with anoxo group.

In other preferred embodiments R₅ is a 6-membered aryl ring, preferablyphenyl.

As used herein, the term “alkyl” means a linear or branched saturatedaliphatic hydrocarbon group having a single radical and 1–10 carbonatoms. Examples of alkyl groups include methyl, propyl, isopropyl,butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl. A branchedalkyl means that one or more alkyl groups such as methyl, ethyl orpropyl, replace one or both hydrogens in a —CH₂— group of a linear alkylchain.

The term “cycloalkyl” means a non-aromatic mono- or multicyclichydrocarbon ring system having a single radical and 3–12 carbon atoms.Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl,and cyclohexyl. Exemplary multicyclic cycloalkyl rings include adamantyland norbornyl.

The term “alkenyl” means a linear or branched aliphatic hydrocarbongroup containing a carbon-carbon double bond having a single radical and2–10 carbon atoms. A “branched” alkenyl means that one or more alkylgroups such as methyl, ethyl or propyl replace one or both hydrogens ina —CH₂— or —CH═ linear alkenyl chain. Exemplary alkenyl groups includeethenyl, 1- and 2-propenyl, 1-, 2- and 3-butenyl, 3-methylbut-2-enyl,2-propenyl, heptenyl, octenyl and decenyl.

The term “cycloalkenyl” means a non-aromatic monocyclic or multicyclichydrocarbon ring system containing a carbon-carbon double bond having asingle radical and 3 to 12 carbon atoms. Exemplary monocycliccycloalkenyl rings include cyclopropenyl, cyclopentenyl, cyclohexenyl orcycloheptenyl. An exemplary multicyclic cycloalkenyl ring is norbomenyl.

The term “aryl” means a carbocyclic aromatic ring system containing one,two or three rings which may be attached together in a pendent manner orfused, and containing a single radical. Exemplary aryl groups includephenyl and naphthyl.

The term “heteroaryl” means unsaturated heterocyclic radicals, whereinheterocyclic is as previously described. Exemplary heteroaryl groupsinclude unsaturated 3 to 6 membered heteromonocyclic groups containing 1to 4 nitrogen atoms, such as pyrrolyl, pyridyl, pyrimidyl, andpyrazinyl; unsaturated condensed heterocyclic groups containing 1 to 5nitrogen atoms, such as indolyl, quinolyl, isoquinolyl; unsaturated 3 to6-membered heteromonocyclic groups containing an oxygen atom, such asfuryl; unsaturated 3 to 6 membered heteromonocyclic groups containing asulfur atom, such as thienyl; unsaturated 3 to 6 memberedheteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, such as oxazolyl; unsaturated condensed heterocyclicgroups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such asbenzoxazolyl; unsaturated 3 to 6 membered heteromonocyclic groupscontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such asthiazolyl; unsaturated condensed heterocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl. The term“heteroaryl” also includes unsaturated heterocyclic radicals, whereinheterocyclic is as previously described, in which the heterocyclic groupis fused with an aryl group, in which aryl is as previously described.Exemplary fused radicals include benzofuran, benzdioxole andbenzothiophene.

As used herein, the term “patient” includes both human and othermammals.

As used herein, the term “halogen” includes fluoride, bromide, chloride,iodide or alabamide.

As used herein, the term “specificity” with respect to opioid receptorsis obtained by dividing the K_(l) (nM) at one opioid receptor by theK_(i) (nM) at another receptor (higher K_(l)/lower K_(i).

The invention disclosed herein is meant to encompass allpharmaceutically acceptable salts thereof of the disclosed compounds.The pharmaceutically acceptable salts include, but are not limited to,metal salts such as sodium salt, potassium salt, secium salt and thelike; alkaline earth metals such as calcium salt, magnesium salt and thelike; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like;inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts such as arginate, asparginate, glutamate and the like.

The invention disclosed herein is also meant to encompass all prodrugsof the disclosed compounds. Prodrugs are considered to be any covalentlybonded carriers which release the active parent drug in vivo.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfor example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled compound of the invention, administering it parenterallyin a detectable dose to an animal such as rat, mouse, guinea pig,monkey, or to man, allowing sufficient time for metabolism to occur andisolating its conversion products from the urine, blood or otherbiological samples.

The invention disclosed herein is also meant to encompass the disclosedcompounds being isotopically-labelled by having one or more atomsreplaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Some of the compoundsdisclosed herein may contain one or more asymmetric centers and may thusgive rise to enantiomers, diastereomers, and other stereoisomeric forms.The present invention is also meant to encompass all such possible formsas well as their racemic and resolved forms and mixtures thereof. Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended to include both E and Z geometric isomers. All tautomers areintended to be encompassed by the present invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image rotates the plane of polarized light inthe opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

Certain preferred compounds according to the invention include:

1-benzylamino-3-dibutylamino-propyl;

1-[1-benzyl-1-(2-phenyl-1-oxo-ethyl)-amino]-2-diethylamino-ethyl;

1-[1-benzyl-1-(2-phenyl-1-oxo-ethyl)-amino]-2-dibutylamino-propyl; andpharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention can be administered to anyonerequiring modulation of the μ receptors. Administration may be orally,topically, by suppository, inhalation, or parenterally.

The present invention also encompasses all pharmaceutically acceptablesalts of the foregoing compounds. One skilled in the art will recognizethat acid addition salts of the presently claimed compounds may beprepared by reaction of the compounds with the appropriate acid via avariety of known methods.

Various oral dosage forms can be used, including such solid forms astablets, gelcaps, capsules, caplets, granules, lozenges and bulk powdersand liquid forms such as emulsions, solution and suspensions. Thecompounds of the present invention can be administered alone or can becombined with various pharmaceutically acceptable carriers andexcipients known to those skilled in the art, including but not limitedto diluents, suspending agents, solubilizers, binders, disintegrants,preservatives, coloring agents, lubricants and the like.

When the compounds of the present invention are incorporated into oraltablets, such tablets can be compressed, tablet triturates,enteric-coated, sugar-coated, film-coated, multiply compressed ormultiply layered. Liquid oral dosage forms include aqueous andnonaqueous solutions, emulsions, suspensions, and solutions and/orsuspensions reconstituted from non-effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, coloring agents, and flavoring agents. When thecompounds of the present invention are to be injected parenterally, theymay be, e.g., in the form of an isotonic sterile solution.Alternatively, when the compounds of the present invention are to beinhaled, they may be formulated into a dry aerosol or may be formulatedinto an aqueous or partially aqueous solution.

In addition, when the compounds of the present invention areincorporated into oral dosage forms, it is contemplated that such dosageforms may provide an immediate release of the compound in thegastrointestinal tract, or alternatively may provide a controlled and/orsustained release through the gastrointestinal tract. A wide variety ofcontrolled and/or sustained release formulations are well known to thoseskilled in the art, and are contemplated for use in connection with theformulations of the present invention. The controlled and/or sustainedrelease may be provided by, e.g., a coating on the oral dosage form orby incorporating the compound(s) of the invention into a controlledand/or sustained release matrix.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms, are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference herein. Techniques andcompositions for making solid oral dosage forms are described inPharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz,editors) 2nd edition, published by Marcel Dekker, Inc., incorporated byreference herein. Techniques and compositions for making tablets(compressed and molded), capsules (hard and soft gelatin) and pills arealso described in Remington's Pharmaceutical Sciences (Arthur Osol,editor), 1553B1593 (1980), incorporated herein by reference. Techniquesand composition for making liquid oral dosage forms are described inPharmaceutical Dosage Forms: Disperse Systems, (Lieberman, Rieger andBanker, editors) published by Marcel Dekker, Inc., incorporated hereinby reference.

When the compounds of the present invention are incorporated forparenteral administration by injection (e.g., continuous infusion orbolus injection), the formulation for parenteral administration may bein the form of suspensions, solutions, emulsions in oily or aqueousvehicles, and such formulations may further comprise pharmaceuticallynecessary additives such as stabilizing agents, suspending agents,dispersing agents, and the like. The compounds of the invention may alsobe in the form of a powder for reconstitution as an injectableformulation.

The dose of the compounds of the present invention is dependent upon theaffliction to be treated, the severity of the symptoms, the route ofadministration, the frequency of the dosage interval, the presence ofany deleterious side-effects, and the particular compound utilized,among other things.

The following examples illustrate various aspects of the presentinvention, and are not to be construed to limit the claims in any mannerwhatsoever.

EXAMPLES 1–3

1-benzylamino-3-dibutylamino-propyl (Example 1);

1-[1-benzyl-1-(2-phenyl-1-oxo-ethyl)-amino]-2-dibutylamino-ethyl(Example 2); and

1-[1-benzyl-1-(2-phenyl-1-oxo-ethyl)-amino]-2-diethylamino-ethyl(Example 3).

The above compounds were synthesized according to the followingsynthetic scheme and general procedure:

Compound 3 Example 1

To a solution of benzaldehyde (1, 3.1 g, 29.5 mmol) in anhydrousmethanol was added 3-(dibutylamino)propylamine (2, 5 g, 26.8 mmol).After stirring 1 h in the presence of 3 Å molecular sieves, sodiumborohydride (1.0 g, 26.8 mmol) was added. After stirring another 16hours, the reaction was filtered, and the sieves were washed withdichloromethane. Water was added, and the phases were separated. Theaqueous phase was made basic by addition of 15% aqueous NaOH, and it wasthen extracted with dichloromethane. The combined organic extracts werewashed with water, washed with brine, dried with sodium sulfate, andconcentrated. Silica gel chromatography eluting with 20:2:1 hexane-ethylacetate-triethylamine provided compound 3 as a colorless oil: ¹H NMRdata (300 MHz, CDCl₃): δ 0.88 (t, 6H, J=7.0 Hz), 1.26 (m, 4H), 1.37 (m,4H), 1.64 (m, 2H), 2.35 (t, 4H, J=8.0 Hz), 2.43 (t, 2H, J=7.0 Hz), 2.64(t, 2H, J=6.8 Hz), 3.75 (s, 2H), 7.15–7.40 (m, 5H).

Compound 4 Example 2

To a solution of compound 3 (500 mg, 1.81 mmol) in anhydrous THF wasadded phenylacetic acid (246 mg, 1.81 mmol), EDCI (520 mg, 2.71 mmol),and DMAP (442 mg, 3.62 mmol), and the reaction mixture was allowed tostir 15 h. Water and dichloromethane were added, and the layers wereseparated. The aqueous phase was extracted with dichloromethane. Thecombined organic extracts were washed with 5% HCl, washed with saturatedaqueous sodium bicarbonate, washed with water, washed with brine, driedwith sodium sulfate, and concentrated. Silica gel chromatography elutingwith 20:2:1 hexane-ethyl acetate-triethylamine provided compound 4 as acolorless oil: ¹H NMR data (300 MHz, CDCl₃): (2 rotamers) δ 2.20 (m,6H), 1.25–1.90 (m, 8H), 1.58 (m, 1.2H), 1.68 (m, 0.8H), 2.15 (m, 6H),3.25 (t, 1.2H, J=7.4 Hz), 3.40 (t, 0.8H, J=6.9 Hz), 3.68 (s, 0.8H), 3.80(s, 1.2H), 4.50 (s, 0.8H), 4.63 (s, 1.2H), 7.05–7.45 (m, 10H).

Compound 6 Example 3

To a solution of N′-benzyl-N,N-dimethylethylenediamine (5, 500 mg, 2.8mmol) in anhydrous THF was added phenylacetic acid (382 mg, 2.8 mmol),EDCI (805 mg, 4.2 mmol), and DMAP (684 mg, 5.6 mmol), and the reactionmixture was allowed to stir 15 h. Water and dichloromethane were added,and the layers were separated. The aqueous phase was extracted withdichloromethane. The combined organic extracts were washed with 5% HCl,washed with saturated aqueous sodium bicarbonate, washed with water,washed with brine, dried with sodium sulfate, and concentrated. Silicagel chromatography eluting with 10:2:1 hexane-ethylacetate-triethylamine provided compound 6 as a colorless oil: ¹H NMRdata (300 MHz, CDCl₃): (2 rotamers) δ 2.15 (s, 2.4H), 2.20 (s, 3.6H),2.29 (t, 0.8H, J=6.9 Hz), 2.44 (t, 1.2H, J=7.4 Hz), 3.30 (t, 0.8H, J=6.9Hz), 3.48 (t, 1.2H, J=7.4 Hz), 3.70 (s, 1.2H), 3.81 (s, 0.8H), 4.57 (s,1.2H), 4.64 (s, 0.8H), 7.10–7.35 (m, 10H).

The general procedures disclosed above can be modified in order tosynthesize the other preferred compounds of the invention.

Example 4

Affinity at the μ, k and δ receptors for preferred compounds wasobtained according to the following assays:

Mu, kappa or delta opioid receptor membrane solution was prepared bysequentially adding final concentrations of 0.075 μg/μl of the desiredmembrane protein, 10 μg/ml saponin, 3 μM GDP and 0.20 nM [³⁵S]GTPγS tobinding buffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice.The prepared membrane solution (190 μl/well) was transferred to96-shallow well polypropylene plates containing 10 μl of 20×concentrated stock solutions of agonist prepared in DMSO. Plates wereincubated for 30 min at room temperature with shaking. Reactions wereterminated by rapid filtration onto 96-well Unifilter GF/B filter plates(Packard) using a 96-well tissue harvester (Brandel) and followed bythree filtration washes with 200 μl ice-cold binding buffer (10 mMNaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates were subsequently driedat 50° C. for 2–3 hours. Fifty μl/well scintillation cocktail(MicroScint20, Packard) was added and plates were counted in a PackardTop-Count for 1 min/well.

Data were analyzed using the curve fitting functions in GraphPad PRISM™,v. 3.0 and the results are set forth in table 1 below:

TABLE 1 calc K_(i) (nM) Compound μ k δ₂1-[1-benzyl-1-(2-phenyl-1-oxo-ethyl)-amino]-2- 40 3500 >10,000dibutylamino-ethyl

1. A compound of the formula (I):

wherein R₁ is selected from the group consisting of C₁ or C₃₋₁₀ alkyl,C₂₋₁₀ alkenyl and C₂₋₁₀ alkenylene; R₂ and R₃ are independently selectedfrom the group consisting of C₄₋₁₀ alkyl, C₂₋₁₀ alkenyl and C₂₋₁₀alkenylene R₄ is selected from the group consisting of a bond and C₁₋₁₀alkyl, C₂₋₁₀ alkenyl and C₂₋₁₀ alkenylene, said alkyl, alkenyl andalkenylene optionally substituted with 1–3 halogen or oxo groups; R₅ isselected from the group consisting of hydrogen, a 5 or 6 memberedaromatic or heteroaromatic group, and a C₃₋₁₂ cycloalkyl; R₆ is C₃₋₁₂cycloalkyl; and n is an integer from 0–3; or a pharmaceuticallyacceptable salt thereof.
 2. A compound of claim 1 wherein R₂ is butyl.3. A compound of claim 1 wherein R₄ is selected from a bond, methyl, orethyl, wherein the methyl and ethyl are optionally substituted with anoxo group.
 4. A compound of claim 1, wherein R₅ is phenyl.
 5. A compoundof claim 1 selected from 1-benzylamino-3-dibutylamino-propyl;1-[1-benzyl-1-(2-phenyl-1-oxo-ethyl)-amino]-2-diethylamino-propyl; andpharmaceutically acceptable salts thereof.
 6. A pharmaceuticalcomposition comprising a compound of claim 1 and at least onepharmaceutically acceptable excipient.